INTERNATIONAL JOURNAL OF PHARMACEUTICAL … 1215.pdfDimenhydrinate, cyclizine, meclozine, and...

Research Article CODEN: IJPRNK ISSN: 2277-8713 Sara S. Barakat, IJPRBS, 2016; Volume 5(1): 111-122 IJPRBS

Available Online at www.ijprbs.com 111

NANOLIPOSOMES CONTAINING PENETRATION ENHANCERS FOR THE INTRANASAL DELIVERY OF THE ANTIEMETIC DIMENHYDRINATE

SARA S. BARAKAT1, MAHA NASR2, SABRY S. BADAWY1, SAMAR MANSOUR2,3

1. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Misr

International University, Egypt

2. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams

University, Egypt.

3. Pharmaceutical Technology Department- German University in Cairo. Egypt.

Accepted Date: 06/02/2016; Published Date: 27/02/2016

Abstract: This study involves the preparation of nanoliposomes containing penetration enhancers (PEVs) for the intranasal delivery of dimenhydrinate (DMH) for rapid treatment of nausea and vomiting. The nanovesicles were prepared using different amounts of phosphatidylcholine and a 1:1 ratio of the penetration enhancers (labrasol and transcutol) using the reverse phase evaporation technique (REV). The PEVs prepared were then characterized for their entrapment efficiency, particle size, zeta potential and polydispersity index (PDI). Their stability following refrigeration storage was also investigated after 3 months. The morphology of the selected formula was examined using transmission electron microscopy (TEM). Results showed that the reverse phase evaporation technique was able to produce vesicles in the nanometer range (59.46 ± 1.6 nm to 266.5 ± 20.5 nm), which were also able to incorporate dimenhydrinate at high entrapment levels (ranging from 82.95-95.35%). The formula prepared using large amount of phosphatidylcholine showed maximum stability after storage, manifested by insignificant changes in particle size, zeta potential and polydispersity index (P<0.05). TEM confirmed the nanosize and spherical morphology of the selected vesicular formula. These results show that penetration enhancer containing vesicles (PEVs) can be used as a successful carrier for the possible intranasal delivery of dimenhydrinate.

Keywords: dimenhydrinate, intranasal delivery, penetration enhancer containing vesicles, motion sickness.

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Sara S. Barakat, IJPRBS, 2016; Volume 5(1): 111-122



INTRODUCTION

Motion sickness is a syndrome occurring upon exposure to certain types of motion, and

resolving after its cessation [1]. The major signs of motion sickness include nausea, salivation

and vomiting. However, nausea is the hallmark symptom for motion sickness. [2]

It was postulated that motion sickness was mainly due to cholinergic stimulation, while the

adrenergic activation suppresses it. That’s why the central anticholinergics are the most

effective anti-motion sickness drugs in addition to antihistamines with antimuscarinic activity.

Dimenhydrinate, cyclizine, meclozine, and promethazine are the antihistamine agents most

widely used for prophylaxis and active treatment of motion sickness [3].

Dimenhydrinate (DMH) is an OTC drug used for the prevention and treatment of nausea,

vomiting, dizziness, and vertigo associated with motion sickness. It is used for the prevention of

postoperative vomiting and drug induced vomiting [4,5]. DMH has an antihistaminic H1 and

antimuscarinic action acting mainly in the central vestibular nuclei and vomiting center. Despite

its usefulness when administered via the oral route, rapid action requires the use of an

alternative route that allows the transmission of the drug directly to the brain; a virtue which

can be achieved using the intranasal route, owing to the direct nose to brain shunt provided by

the olfactory region [6].

Vesicular delivery systems are one of the most promising systems designed for targeting and

controlling the delivery of drugs. Vesicles are spheres consisting of one or more concentric lipid

bilayers that are formed by placing certain amphiphilic molecules such as phospholipids or

surfactants in water. Liposomes are type of vesicles consisting of one or more concentric lipid

bilayers separated by water or aqueous buffer compartments, with size ranging from 10

nanometers to 20 micrometers. Recently, Penetration enhancer containing vesicles (PEVs) have

been developed as a new elastic vesicular system prepared using penetration enhancers such

as oleic acid, Transcutol® and Labrasol® [7,8]. Therefore, the aim of the current work was to test

the feasibility of incorporating the antiemetic drug DMH within PEVs for possible intranasal

delivery for rapid antiemetic effects.

MATERIALS AND METHODS

Materials

Dimenhydrinate was kindly supplied by Alkahira Pharmaceuticals & Chemical Industries

Company, Cairo, Egypt. Sodium chloride (NaCl), Sodium dihydrogen orthophosphate 1 –

hydrate, Polyethylene glycol 400 (PEG), Disodium hydrogen orthophosphate anhydrous,



methanol, chloroform and Diethyl ether were purchased from El-Nasr Chemical Company, Cairo,

Egypt. Dialysis membrane (Spectra / Por) 12.000 – 14.000 molecular weight Cut off was

purchased from Spectrum Laboratories Inc, Rancho Dominguez, Canada. Capryl-caproyl

macrogol 8-glyceride (Labrasol®) and 2-(2-ethoxyethoxy) ethanol (Transcutol®) were kindly

gifted by Gattefosse' Company, France. Phosphatidylcholine (Epikuron 200) was kindly provided

by Cargill Texturizing solutions, Deutschland GmbH & Co., Hamburg, Germany. Acetyl Uranil

(Uranyl acetate -2- hydrate) was purchased from Allied signal, Riedel- dehaen, Germany).

Methods

Preparation of dimenhydrinate loaded PEVs

The dimenhydrinate-loaded PEVs were prepared using the reversed phase evaporation

technique (REV) using different amounts of phospholipid in the presence of the penetration

enhancers labrasol and transcutol at a ratio of 1:1, as shown in table (1) [9]. The phospholipids

were dissolved in chloroform: methanol mixture (2:1, v/v) [10]; in a round bottomed flask,

followed by evaporation of the organic solvent mixture using a rotary evaporator (Rotavapor R-

210/215, Buchi, Switzerland) at 40°C resulting in the formation of lipid thin film on the inner wall

of the flask. The film was re-dissolved in 12 ml diethyl ether, followed by the addition of 6 ml

phosphate buffer saline pH 7.4 [9,11] containing different amounts of DMH solubilized in 0.5 ml

PEG 400, with the penetration enhancers labrasol and transcutol included in the buffer at a ratio

of 1:1 v/v. The system was swirled by hand, and the formed emulsion was then placed in the

rotary evaporator where the organic solvent was removed under reduced pressure to fully

remove the organic solvent followed by the addition of 4 ml phosphate buffered saline. The

resultant vesicular dispersion was then sonicated at 40°C for one hour using sonicator

(Transsonic model: TI-H 5, Germany) to reduce their particle size [12]. The composition of the

prepared liposomal formulations is demonstrated in table (1).

Separation of unentrapped dimenhydrinate from the prepared PEVs

Purification of PEVs from the non-encapsulated drug was done by exhaustive dialysis, in which

PEVs formulae were placed in a dialysis tubing (Dialysis membrane Spectra / Por 12.000 – 14.000

molecular weight). The dialysis was carried out against 1000 ml distilled water for 2 hours [13],

which was found appropriate for the removal of the non-entrapped dimenhydrinate in the

medium, as shown by preliminary experiments (data not shown).

Characterization of the prepared PEVs

Determination of dimenhydrinate entrapment efficiency in the PEVs



To determine the amount of dimenhydrinate entrapped in the dialyzed vesicles, the vesicles

were disrupted using methanol. Five hundred microliters of PEVs were mixed with 4.5 ml of

methanol to obtain a clear solution, which was covered well with a parafilm to prevent methanol

evaporation. The concentration of dimenhydrinate in methanol was determined

spectrophotometrically at the predetermined λmax after appropriate dilution using ultraviolet

spectrophotometer (Evisa-Shimadzu model: UV-1650PCUV-1650PC, Europe). No interference

was found from PEVs at this wavelength.

The entrapment efficiency values were further confirmed by measuring the amount of free

dimenhydrinate obtained in the distilled water, which was then subtracted from the total

amount initially added in the formula to determine the amount of dimenhydrinate entrapped in

the vesicles. The entrapment efficiency was calculated through the following relationship [14,

15]

Entrapment Efficiency Percentage = Entrapped drug x 100 (Equation 1)

Total drug

Determination of the particle size and zeta potential of PEVs

The size, polydispersity index (PDI) and charge of the prepared dimenhydrinate PEVs were

determined by photon correlation spectroscopy (PCS) using Zetasizer nano-ZS (Nano ZS 3600,

Malvern Instruments Ltd., WorcesterShire, UK), after appropriate dilution [13,16,17].

Stability study for the prepared vesicles

The prepared dimenhydrinate loaded PEVs were stored for three months at refrigeration

temperature 2-8ºC. After the three months storage period, the samples were inspected visually

for their homogeneity and consistency. The particle size, zeta potential and polydispersity index

(PDI) of the PEVs were also re-measured.

Determination of the morphology of PEVs using transmission electron microscope (TEM)

The characterization of the vesicles shape was done for the selected PEVs formula by

transmission electron microscopic (TEM) analysis (JEM-100 S, Joel, Tokyo, Japan) [18]. The

analysis was done by depositing one drop of the diluted sample on a film coated 200-mesh

copper grid, followed by uranyl acetate staining (1%) and drying [8]. Before examination any

excess fluid was removed with filter paper.



Statistical analysis

The obtained data was statistically analyzed using Graph pad Instat program. Data were

expressed as the mean ± standard deviation (S.D.). Comparison of the mean values was done

using one way analysis of variance (ANOVA), followed by Tukey – Kramer Multiple Comparisons

Test. Statistical significance was set at p-value ≤ 0.05. All measurements were conducted in

triplicate.

RESULTS AND DISCUSSION

Determination of dimenhydrinate entrapment efficiency in the PEVs

PEVs were prepared using the reversed phase evaporation technique (REV) using soybean

phosphatidylcholine as bilayer forming lipid. The choice of the method was based on the fact

that REV was more suited for encapsulation of hydrophilic drugs, such as DMH with a log P -0.39

[19, 20]. Although the effect of penetration enhancers in promoting the drug absorption is well

established; the precise mechanism of their action is not known, but it is suggested that they

promote drug absorption by increasing the membrane fluidity, expanding the dimensions of the

paracellular pathway to solute transport and also they form reverse micelles in the cell

membrane thus creating transient pores in the membrane [21]. The selected penetration

enhancers to be incorporated in the vesicles were labrasol and transcutol.

Labrasol (capryl-caproyl macrogol 8-glyceride) is a well-defined mixture of mono-, di- and

triglycerides and mono- and di-fatty acid esters of polyethyleneglycol, with caprylic and capric

acids being the predominant fatty acids. It was suggested that labrasol has a tight junction

opening action leading to increased membrane permeability for water-soluble drugs [22]. On

the other hand, transcutol (diethylene glycol monoethylether) is an ethylene oxide derivative

with a long history of safe use as a solvent in many products including pharmaceuticals,

cosmetics, and food applications, thus, presenting itself as strong solubilizer with low toxicity

[23]. Additionally, the presence of Transcutol HP in intranasal formulations was found

advantageous in enhancing the bioavailability of drugs [24]. PEG 400; which is also a penetration

enhancer on its own, was incorporated in the hydrating buffer for the solubilization of DMH. It

was reported to enhance the penetration of drugs intranasally by improving the vesicular bilayer

fluidity thus facilitating the penetration of the highly fluidized vesicles [25].

The EE% results of the prepared PEVs are shown in table (2). The EE% of dimenhydrinate in PEVs

ranged from 78.915 ± 3.46 % to 95.35± 0.15%. These acceptable values of the entrapment

efficiency (EE%) of the prepared formulae could be attributed to the polar nature of

dimenhydrinate (log p = - 0.39) which allows it to be entrapped in the large hydrophilic core of



the PEVs which are prepared by the reverse phase evaporation technique. The aforementioned

technique is known to result in a high aqueous space-to-lipid ratio and increase the capability of

the vesicles to entrap a large percentage of hydrophilic drugs [19, 20, 26]. The high entrapment

efficiencies can also be ascribed to the presence of the penetration enhancers labrasol and

transcutol which possess hydrophilic natures [7].

By further inspection of EE% values in table (2) and figure (1), it was clear that in formulae (1-3)

containing the same amount of phospholipid (300 mg), the increase in the amount of drug from

50 mg in formula (1), to 100 and 150 mg in formulae (2) and (3) respectively resulted in a

significant decrease in EE% of DMH (P<0.05). This could be attributed to the higher

concentration gradient of DMH created by its increase in concentration, resulting in more

diffusion of the drug upon conduction of dialysis. The preserving of this EE% upon increasing the

amount of DMH to 200 mg with an accompanying increase in phospholipid amounts to 900 mg

in formula (4), is probably attributed to the increased particle size of the vesicles with increased

phospholipid amounts (to be displayed in the particle size section), creating more space for

accommodation of the drug, leading to significant increase in the loaded DMH amounts.

Figure (1): Effect of the amount of DMH drug on the entrapment efficiency (EE%) of the

prepared PEVs.

0

20

40

60

80

100

120

1 2 3

DM

H E

E%

PEVs formulae

1 (50 mg DMH)

2 (100 mg DMH)

3 (150 mg DMH)



Determination of the particle size and zeta potential of PEVs

The results of the particle size of the vesicles are shown in table (3). The particle size of the

prepared PEVs ranged from 59.46 ± 1.6 nm to 266.5 ± 20.5 nm. The small particle size range of

the vesicles was also reported by other authors who prepared PEVs using labrasol and transcutol

[17, 27, 28]. Formulae 1-3, prepared using different amounts of DMH, displayed non-significant

changes in particle size (P<0.05) (Figure 2). This suggests the solubilized nature of DMH in the

aqueous core of the vesicles rather than the phospholipid bilayer coat. It was also clear that by

increasing the amount of phospholipids the particle size significantly increased (p<0.05), in

which formula (4) prepared using 900 mg phospholipids displayed a particle size of 266.5. This

came in accordance with Jacquot et al., 2014 [29], and could be ascribed to the increase in the

phospholipid bilayer thickness upon increasing its amount in the preparation.

Figure (2): Effect of the amount of DMH on the particle size of the prepared PEVs.

Regarding polydispersity index, all formulae had a generally low PDI values (0.3-0.49), with a

near neutral surface charge, owing to the almost neutral nature of the phospholipids, and the

non-charged nature of the utilized penetration enhancers [31].

Stability study of the prepared DMH PEVs

Table (3) shows the effect of refrigeration storage for 3 months on the particle size, zeta

potential and PDI of the PEVs respectively.

52

54

56

58

60

62

64

66

68

1 2 3

Par

ticl

e s

ize

(n

m)

PEVs formulae

1 (50 mg DMH)

2 (100 mg DMH)

3 (150 mg DMH)



Interestingly, the formulae prepared using 300 mg phospholipids (1-3) displayed a significant

increase in their particle size and PDI upon storage (P<0.05) indicative of vesicular swelling, while

that prepared using 900 mgs phospholipids (4) displayed an insignificant increase in particle size

(p>0.05). This may be explained by the fact that labrasol was reported to cause destabilization

of the phospholipid bilayers, and transcutol was reported to interact with the polar heads of the

phospholipids [8]; with this interaction being accentuated at the low phospholipid:PE ratios

achieved with (1-3). No significant changes in zeta potential was observed for all vesicular

formulations upon storage (P<0.05).

Since formula 4 displayed the best storage properties, it was chosen for morphological

examination using TEM.

Determination of the morphology of PEVs using transmission electron microscope (TEM)

As evident in figure 3, the PEVs displayed spherical morphology, with particle size in the

nanometer range.

Figure (3): TEM micrograph of formula 4 at a magnification of 120000X.



CONCLUSION

Penetration enhancer containing vesicles (PEVs) can be considered as a promising system for

encapsulating the antiemetic dimenhydrinate at high loading values. Their content of labrasol

and transcutol in combination with the reverse phase evaporation technique contributed to

their nanometer size, suggesting their potential for intranasal delivery of dimenhydrinate.

ACKNOWLEDGEMENTS

The authors are grateful to Alkahira pharmaceutical company, Egypt; Gattefosse' Company,

France; Cargill Texturizing solutions, Deutschland GmbH & Co., Hamburg, Germany for their kind

supply of dimenhydrinate, (Labrasol and transcutol) and phosphatidylcholine (Epikuron 200)

respectively.

DECLARATION OF INTEREST

The authors report no conflicts of interest

Table (1): The composition of dimenhydrinate loaded PEVs.

Formulation

code *

Amount of

Drug

(mg)

Total

volume of

PBS pH7.4

(ml)

Amount of Penetration

Enhancer

(ml)

Amount of

phospholipid

(mg)

Labrasol Transcutol

1 50 7.5 1 1 300

2 100 7.5 1 1 300

3 150 7.5 1 1 300

4 200 7.5 1 1 900

Table (2): Entrapment efficiency and drug loading for different DMH loaded PEVs

Formulation code Entrapment efficiency % (EE%)

Mean ± S.D

Loaded amount of

Dimenhydrinate (mg)

1 95.35 ± 0.15 47.68

2 78.915 ± 3.46 78.91

3 82.96 ± 1.95 124.44



4 83.37 ± 2.20 166.74

Table (3): Effect of storage on the stability of the PEVs.

PDI

stability of

the

freshly

prepared

vesicles

PDI

of the

freshly

prepared

vesicles

Zeta

potential

stability of

the vesicles

after 3

months

storage

(mV)

Zeta

potential

of the

freshly

prepared

vesicles

(mV)

P.S.

of the

vesicles after

3 months

storage

(nm)

P.S. of the

freshly

prepared

vesicles (nm)

Formula

Code

0.98 ± 0.02 0.36 ± 0.01 0.976 ± 0.08 0.94 ± 0.64 136 ± 8.3 59.46 ± 1.6 1

1 0.3 ± 0.006 0.414 ± 0.05 0.629 ± 0.08 129 ± 9.42 64.63 ± 1.92 2

0.66 ± 0.05 0.48 ± 0.02 0.593 ± 0.09 0.373 ± 0.11 118 ± 3.5 60.72 ± 2.09 3

0.46 ± 0.14 0.49 ± 0.12 0.61 ± 0.59 0.934 ± 0.56 284.5 ± 16 266.5 ± 20.5 4

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